1. Field of the Invention
The present invention relates to a treatment of ocular hypertension with a synergistic combination comprising (a) a 3,14-dihydro-15-ketoprostaglandin compound and (b) a cholinergic agent.
The compounds used as the component (a) in the present invention are prostaglandin analogues which can be obtained synthetically.
2. Information of Prior Art
Prostaglandins (hereinafter, prostaglandins are referred to as PGs) are members of a class of organic carboxylic acid that are contained in human and most other mammalian tissues or organs and that exhibit a wide range of physiological activities. Naturally occurring PGs possess as a common structural feature the prostanoic acid skeleton: ##STR1## Some synthetic analogues have somewhat modified skeletons. The primary PGs are classified based on the structural feature of the five-membered cycle moiety into PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs, and also on the presence or absence of unsaturation and oxidation in the chain moiety as:
Subscript 1 - - - 13,14-unsaturated-15-OH PA1 Subscript 2 - - - 5,6- and 13,14-diunsaturated-15-OH PA1 Subscript 3 - - - 5,6- 13,14- and 17,18-triunsaturated-15-OH PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a cholinergic agent PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a cholinergic agent PA1 (a) a 13,14-dihydro-15-ketoprostaglandin compound, and PA1 (b) a cholinergic agent PA1 A commercially available (-)-Corey lactone, which is used as a starting material, is subjected to Collins oxidation to give an aldehyde. The aldehyde is allowed to react with dimethyl (2-oxoalkyl)phosphonate anion to give an .alpha., .beta.-unsaturated ketone, and the resultant is reduced to ketone. The carbonyl group of the ketone is allowed to react with a diol to give a ketal, thereby protected, then a corresponding alcohol is obtained by elimination of the phenylbenzoyl group, and the resulting hydroxy group is protected with dihydropyran to give a tetrapyranyl ether. Thus, precursors of PGs wherein the .omega.-chain is 13,14-dihydro-15-keto-alkyl can be obtained. PA1 PGA obtained by Jones oxidation of the hydroxy group at the C-9 position of the 11-tosylate is allowed to react with a dimethyl copper complex to give 11-dehydroxy-11-methyl-PGE. Alternatively, an alcohol obtained after elimination of p-phenylbenzoyl group is converted to a tosylate. An unsaturated lactone obtained by DBU treatment of the tosylate is converted to a lactol. After introduction of an .alpha.-chain using Wittig reaction, the resulting alcohol (C-9 position) is oxidized to give PGA. PGA is allowed to react with dimethyl copper complex to give 11-dehydroxy-11-methyl-PGE. The resultant is reduced using sodium borohydride and the like to give 11-dehydroxy-11-methyl-PGF. PA1 11-dehydroxy-11-hydroxymethyl-PGE is obtained by a benzophenone-sensitized photoaddition of methanol to PGA. The resultant is, for example, reduced using sodium borohydride to give 11-dehydroxy-11-hydroxymethyl-PGF. PA1 Commercially available (-)-Corey lactone (1) (7 g) was subjected to Collins oxidation in dichloromethane to give aldehyde (2). The resultant was allowed to react with dimethyl (2-oxononyl)phosphonate (4.97 g) anion to give 1S-2-oxa-3-oxo-6R-(3,3-ethylendioxy-1-trans-decenyl)-7R-(4-phenylbenzoylox y)-cis-bicyclo[3.3.0]-octane (3). PA1 Unsaturated ketone (3) (7.80 g) was reduced in ethyl acetate (170 ml) using 5% Pd/C under hydrogen atmosphere. The product obtained after the usual work-up (4) was used in the following reaction. PA1 Saturated ketone (4) was converted to ketal (5) in dry benzene (150 ml) using ethylene glycol and p-toluenesulfonic acid (catalytic amount). PA1 To a solution of ketal (5) in absolute methanol (150 ml) was added potassium carbonate (2.73 g). The mixture was stirred overnight at room temperature. After neutralization with acetic acid, the resultant was concentrated under reduced pressure. The resulting crude product was extracted with ethyl acetate. The organic layer was washed with a dilute aqueous solution of sodium bicarbonate and a saline, and dried. The crude product obtained after evapolation was chromatographed to give alcohol (6). Yield; 3.3 g PA1 Alcohol (6) (0.80 g) was reduced in dry toluene (8 ml) using DIBAL-H at -78 .degree. C. to give lactol (7). PA1 A DMSO solution of lactol (7) was added to ylide prepared from (4-carboxybutyl)triphenylphosphonium bromide (3.65 g). The reaction mixture was stirred overnight to give carboxylic acid (8). PA1 Carboxylic acid (8) was converted to 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2 .alpha. isopropyl ester (9) using DBU and isopropyl iodide in acetonitrile. PA1 13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2 .alpha. isopropyl ester (9) (0.71 g) was kept in acetic acid/THF/water (3/1/1) at 40 .degree. C. for 3 hours. The crude product obtained after concentration under reduced pressure was chromatographed to give 13,t4-dihydro-15-keto-20-ethyl-PGF.sub.2 .alpha. isopropyl ester (10). PA1 A solution of 13,14-dihydro-15-keto-20-ethyl-PGF.sub.2 .alpha. isopropyl ester (10) (0.125 g) and p-toluenesulfonyl chloride (0.112 g) in pyridine (5 ml) was maintained at 0.degree. C. for 2 days According to the usual work-up, osylate (11) was obtained. PA1 13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-PGF.sub.2 .alpha. isopropyl ester (9) (3.051 g) was dissolved in dry N,N-dimethylformamide (25 ml), t-butyldimethylsilyl chloride (1.088 g) and imidazole (0.49 g) was added thereto. The resultant was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was chromatographed to give 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGF.su b.2 .alpha. isopropyl ester (13). PA1 13,14-Dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGF.sub .2 .alpha. isopropyl ester (13) (1.257 g) was subjected to Jones oxidation at -40 .degree. C. After the usual work-up, the resulting crude product was chromatographed to give 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGE.su b.2 .alpha. isopropyl ester (14). PA1 To a solution of 13,14-dihydro-15,15-ethylenedioxy-20-ethyl-11-t-butyldimethylsiloxy-PGE.su b.2 isopropyl ester (14) in acetonitrile was added hydrofluoric acid (46% aqueous solution). The mixture was stirred at room temperature for 40 minutes. The crude products obtained after usual work-up was chromatographed to give 13,14-dihydro-15-keto-20-ethyl-PGE.sub.2 isopropyl ester (15).
Further, PGFs are sub-classified according to the configuration of hydroxy group at position 9 into .alpha.-(hydroxy group being in the alpha configuration) and .beta.-(hydroxy group being in the beta configuration).
It has been known that Pilocarpine inhibit the ocular pressure lowering activity of PGF.sub.2 .alpha. (Ganka MOOK No. 40, page 227, FIG. 10).
On the other hand, the fact that the above component (a) have ocular hypotensive activity has been known by Japanese Patent Publication No. A-108/1990. The publication discloses, on page 9, column 3, lines 3-2 from bottom, that 13,14-dihydro-15-keto-PGs, including the above component, can be co-used with Pilocarpine or Carbachol, both being examples of the component (b) in the present invention (and these are known as agents for treating glaucoma). The disclosure, however, unfocusingly refers to the possibility of co-use of 13,14-dihydro-15-keto-PGs and Pilocarpine or Carbachol. In contrast, when PGF.sub.2 .alpha. (Ganka MOOK) is analogized with the component (a), it is expected that the cholinergic agents such as Pilocarpine inhibit the ocular pressure lowering effect of the component (a) if they are co-administered.
After an extensive study on the possibility that the effect of the component (a) in the present invention is improved by combining it with a variety of compounds, the present inventor has surprisingly discovered that the effect of the component (a) is significantly improved and side-effect is decreased by co-administration with cholinergic agents such as Pilocarpine. Said discovery leads to the present invention.